Major depressive disorder (MDD; depression) is a complex and costly mental health disorder that affects a significant portion of the population and burdens individuals, their families, and society. Available pharmacotherapies for MDD often take weeks to take effect, and even then a substantial proportion of individuals do not respond to treatment. In addition to mood disruption, depression also can cause concomitant cognitive impairment. This decreases a patient?s chance of success with cognitive behavioral therapy (CBT) as well. We have identified a new potential therapeutic target, the glucagon-like peptide-1 receptor (GLP-1R), activation of which may alleviate both mood and cognitive symptoms. The ventral dentate gyrus (DG) of the hippocampus promotes neurogenesis and produces antidepressant-like effects, and the dorsal DG contributes to spatial memory and cognition. GLP-1R activation appears to contribute to both of these functions, and GLP- 1Rs are located in both the dorsal and ventral DG. We therefore hypothesize that GLP-1R activation will have antidepressant and pro-cognitive functions, and that these will be specific to the ventral and dorsal regions of the DG, respectively. Because women are affected more by MDD than men, and because preliminary data suggest sex differences in GLP-1R modulation of cognition, we will study both male and female mice in these studies. Our studies will establish the therapeutic efficacy of GLP-1R ligands in the treatment of depression- induced cognitive decline. Since GLP-1R agonists are already prescribed for other indications, this proposal will establish whether this ?already drugged? target might be efficacious in treating mood disorders and could quickly translate into new clinical applications for already-approved drugs. Our data will also lead to a more nuanced understanding of how distinct hippocampal circuits concurrently regulate specific aspects of cognition and mood and lead to a better understanding of the pathophysiology of MDD.